Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.     

Effectiveness of gentamicin-impregnated cement in the prevention of deep wound infection after primary total knee arthroplasty.

Effectiveness of gentamicin-impregnated cement in preventing deep wound infection after total knee arthroplasty (TKA) was estimated using data from prospective surveillance. In multivariate analysis, the protective effect of gentamicin-impregnated cement on the development of infection was close to the limit of significance. Gentamicin-impregnated cement may prevent TKA infections.     

Sonography of a human jackstone calculus.

Jackstone calculi are urinary tract stones that have a specific appearance resembling toy jacks. They are almost always composed of calcium oxalate dihydrate and may be found in the urinary bladder or rarely in the upper urinary tract. Their appearance on plain radiographs and computed tomography (CT) in human patients has been well described. They have also been imaged in several species of animals. However, our review of the English medical literature revealed no previous report in which a jackstone calculus had been identified on the sonographic examination of a human patient. We report a case in which a large jackstone calculus was incidentally detected during abdominal sonography in a 75-year-old man.     

Relationship between dynamic balance and self-reported handicap in patients who have unilateral peripheral vestibular loss.

OBJECTIVE: The purpose of this study was to investigate whether Dizziness Handicap Inventory (DHI) score is related to postural performance as assessed by dynamic posturography. STUDY DESIGN: Retrospective study. SETTING: Outpatient in a tertiary referral center. PATIENTS: Ninety-two complete unilateral vestibular loss patients, categorized into 3 groups according to the postlesion stage: 1 to 2 months (n = 32; age, 47.6 +/- 10.7 yr), 4 to 7 months (n= 23; 47.1 +/- 8.37 yr), and 1 year and older (n = 37; 49.2 +/- 9.5 yr). MAIN OUTCOME MEASURES: Dizziness Handicap Inventory and dynamic balance measured with a seesaw platform moving either in the anterior-posterior or in the mediolateral direction. RESULTS: The mean DHI score was 25.8 +/- 18.7 and the range was 0 to 68. Dizziness Handicap Inventory scores did not differ significantly between the different unilateral vestibular loss groups studied. No difference was detected between the groups for the 3 subscores (emotional, functional, and physical), except that the older-than-1-year group had a significantly higher physical score than the 2 others. No correlation was found between DHI scores and postural indicators for either direction of the platform. However, patients unable to maintain balance when the seesaw platform moved in the mediolateral direction had significantly higher DHI scores than those who did not fall. CONCLUSION: Even if they are not directly related, we suggest that DHI and dynamic posturography are complementary approaches for appreciating the vestibular compensation process and are thus useful for postoperative counseling for vestibular loss patients.     

A randomized trial of low-protein diet in type 1 and in type 2 diabetes mellitus patients with incipient and overt nephropathy.

OBJECTIVE: The efficacy of a low-protein diet in the secondary prevention of diabetic nephropathy is not established in patients with type 1 or type 2 diabetes mellitus. To determine whether a low-protein diet slows the decrease in glomerular filtration rate (GFR) and decreases the albumin excretion rate (AER) in diabetic patients with incipient and overt nephropathy, we performed a 2-year prospective, randomized controlled trial comparing the effects of a low-protein diet (0.8 g/kg/day) with a usual-protein diet. SETTING AND PATIENTS: The study was conducted in a University hospital and included 63 type 1 and type 2 diabetic patients with either incipient or overt nephropathy and mild renal failure (prestudy GFR, 80 +/- 20 mL/min). The primary outcome measures were decreased in GFR and 24-hour AER. RESULTS: In the low-protein-diet group, patients were younger (52 +/- 12 versus 63 +/- 9 years old) and more often were type 2 diabetic. During the follow-up period, according to dietary records the low-protein-diet group consumed 16% +/- 3% of total caloric intakes as compared with 19% +/- 4% in the usual-protein-diet group (P < .02), but 24-hour urinary urea excretions did not differ between the two groups. The 2-year GFR decrease was 7 +/- 11 mL/min in the low-protein-diet group and 5 +/- 15 mL/min in the usual-protein-diet group (P = not significant). AER did not increase significantly in the two diet groups during the follow-up period. Blood pressure and glycemic control were similar in the two groups all along the study. The decrease in GFR and AER were also similar in 6 compliant patients according to dietary records and to 24-hour urinary urea excretions from the low-protein-diet group and in 12 patients from the usual-protein-diet group. CONCLUSIONS: A 2-year low-protein diet did not alter the course of GFR or of AER in diabetic patients with incipient or overt nephropathy receiving renin-angiotensin blockers with strict blood pressure control.     

Enhancement of performance by methyl β-carboline-3-carboxylate, in learning and memory tasks

Benzodiazepines are known to induce a profound anterograde amnesia in man. In this report, it is shown that methyl β-carboline-3-carboxylate (β-CCM), an inverse agonist of the benzodiazepine receptor, has the opposite effect; it enhances performance in learning and memory tasks. Three different learning models were used: habituation to a new environment and passive avoidance in mice and imprinting in chicks. The opposite effects of both β-CCM and the benzodiazepine diazepam were blocked by administration of the benzodiazepine receptor antagonist Ro 15-1788, provicling evidence that the benzodiazepine receptor is involved in these effects.     

Evidence for a glycosaminoglycan on the nudel protein important for dorsoventral patterning of the drosophila embryo.

Dorsoventral patterning of the Drosophila embryo requires Nudel, a large mosaic protein with a protease domain. Previous studies have implicated Nudel's protease domain as the trigger of a proteolytic cascade that activates the Toll signaling pathway to establish dorsoventral polarity in the embryo. However, the function of other regions of Nudel has been unclear. By using two-dimensional gel electrophoresis and site-directed mutagenesis, we have obtained evidence that the N-terminal region of Nudel contains a site for glycosaminoglycan (GAG) attachment that is required for dorsoventral patterning. Disruption of this site blocks a disulfide-based association between N- and C-terminal Nudel polypeptides and proteolytic activation of Nudel's protease domain. We discuss how a GAG chain on Nudel might be required for Nudel protease activation.     

Operative timing and patient survival following distal splenorenal shunt

The importance of "operative timing" in cirrhotic patients with variceal hemorrhage is often underemphasized. To evaluate the effects of immediate versus delayed selective portasystemic decompression on hepatic function, operative mortality, and long-term patient survival, we reviewed the records of 77 patients who underwent distal splenorenal shunts (DSRS) over a 14-year period. A hepatic risk status score was calculated at the time of the index bleed (HRS1) or presentation and again just prior to operation (HRS2). Variables analyzed included age, sex, prior bleeding episodes, time from index bleed to operation, transfusion requirements, and etiology of cirrhosis. Operative mortality rates for immediate versus delayed DSRS were 46.2 per cent and 17 per cent, respectively. HRS improved significantly in elective DSRS patients from 1.46 to 1.30. Predictors of HRS2 included HRS1 and time in days from the index bleed to operation. The most important predictor of early survival for all patients after elective DSRS was the HRS2; however, for patients who underwent elective DSRS and survived, HRS1 was a better predictor of length of survival than HRS2. No other variable analyzed accurately predicted survival. We conclude that HRS can be expected to improve with supportive inhospital therapy; improved HRS at the time of operation is associated with decreased operative mortality; and the extent of liver disease as determined by HRS1 appears to be the chief determinant of long-term patient survival.